Mechanism of Lithium Diisopropylamide-Mediated Substitution of 2,6-Difluoropyridine

摘要

Abstract: Treatment of 2,6-difluoropyridine with lithium diisopropylamide in THF solution at 78 °Cneffects ortholithiation quantitatively. Warming the solution to 0 °C converts the aryllithium to 2-fluoro-6-n(diisopropylamino)pyridine. Rate studies reveal evidence of a reversal of the ortholithiation and a subsequentn1,2-addition via two monomer-based pathways of stoichiometries [ArH•i-Pr2NLi(THF)]n‡ and [ArH•i-nPr2NLi(THF)3]n‡. Computational studies fill in the structural details and provide evidence of a direct substitutionnwithout the intermediacy of a Meisenheimer complex.